WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification " :
C07D 231/38, 403/12, 409/12, 333/36,
307/66
(11) International Publication Number:
(43) International Publication Date:
WO 99/32455
1 July 1999 (01.07.99)
(21) International Application Number:
PCT/US98/26082
(22) International Filing Date:
22 December 1998 (22.12.98)
(30) Priority Data:
08/996,181
22 December 1 997 (22. 1 2.97) US
(71) Applicant: BAYER CORPORATION [US/US]; 100 Bayer
Road, Pittsburgh, PA 15205 (US).
(72) Inventors: DUMAS, Jacques; 821 Beechwood Road, Orange,
CT 06477 (US). KHIRE, Uday; 101 Tanglewood Drive,
Hamden, CT 06518 (US). LO WINGER, Timothy, Bruno;
5-7, #1203 Chitose-cho, Nishinomiya, Hyogo 662-0046
(JP). PAULSEN, Holger, Pahlkestrasse 5, D-42115 Wup-
pertal (DE). RIEDL, Bernd; 13 Cedrus Court, Branford,
CT 06405 (US). SCOTT, William, J.; 210 Saddle Hill
Drive, Guilford, CT 06437 (US). SMITH, Roger, A.; 65
Winterhill Road, Madison, CT 06443 (US). WOOD, Jill,
E,; 72 Pickwick Road, Hamden, CT 06517 (US). HA-
TOUM-MOKDAD, Holia; 43 Joseph Lane, Hamden, CT
06514 (US). JOHNSON, Jeffrey; 213 Leetes Island Road,
Branford, CT 06405 (US). REDMAN, Aniko; 66 E. Street,
Derby, CT 06418 (US). SIBLEY, Robert; 11 87 Mt. Carmel
Avenue, North Haven, CT 06473 (US).
(74) Agents: TRA VERSO, Richard, J. et ah; Millen, White, Zelano
& Branigan, P.C., Suite 1400, Arlington Courthouse Plaza
1, 2200 Clarendon Boulevard, Arlington, VA 22201 (US).
(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU } CZ, DE, DK, EE, ES, FI, GB, GD,
GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW,
ARIPO patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF,
BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN,
TD, TG).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(54) Title: INHIBITION OF RAF KINASE USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS
(57) Abstract
Methods of treating tumors mediated by raf kinase, with substituted urea compounds, and such compounds per se.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL
Albania
ES
Spain
LS
Lesotho
SI
Slovenia
AM
Armenia
FI
Finland
LT
Lithuania
SK
Slovakia
AT
Austria
FR
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LU
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SN
Senegal
AU
Australia
GA
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LV
Latvia
sz
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AZ
Azerbaijan
GB
United Kingdom
MC
Monaco
TD
Chad
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GE
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MD
Republic of Moldova
TG
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BB
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GH
Ghana
MG
Madagascar
TJ
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BE
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GN
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Greece
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TR
Turkey
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HU
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TT
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Benin
IE
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MN
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MR
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BY
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CG
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KE
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NL
Netherlands
YU
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CH
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KG
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NO
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ZW
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CI
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KP
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NZ
New Zealand
CM
Cameroon
Republic of Korea
PL
Poland
CN
China
ICR
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PT
Portugal
cu
Cuba
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Kazakstan
RO
Romania
cz
Czech Republic
LC
Saint Lucia
RU
Russian Federation
DE
Germany
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Liechtenstein
SD
Sudan
DK
Denmark
LIC
Sri Lanka
SE
Sweden
EE
Estonia
LR
Liberia
SG
Singapore
WO 99/32455
PCT/US98/26082
5
Inhibition of RAF Kinase Using Aryl and Heteroaryl Substituted Heterocyclic
Ureas
10
Field of the Invention
This invention relates to the use of a group of aryl ureas in treating raf mediated
diseases, and pharmaceutical compositions for use in such therapy.
15 Background of the Invention
The p21 ras oncogene is a major contributor to the development and progression of
human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann.
Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its
normal, unmutated form, the ras protein is a key element of the signal transduction
20 cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends
Biochem. ScL 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding
protein, and cycling between a GTP -bound activated and a GDP-bound resting form is
strictly controlled by ras' endogenous GTPase activity and other regulatory proteins.
In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and,
25 therefore, the protein delivers constitutive growth signals to downstream effectors
such as the enzyme raf kinase. This leads to the cancerous growth of the cells which
carry these mutants (Magnuson et al. Semin. Cancer Biol 1994, 5, 247-53). It has
been shown that inhibiting the effect of active ras by inhibiting the raf kinase
signaling pathway by administration of deactivating antibodies to raf kinase or by co-
30 expression of dominant negative raf kinase or dominant negative MEK, the substrate
of raf kinase, leads to the reversion of transformed cells to the normal growth
phenotype (see: Daum et al. Trends Biochem. Set 1994, 19, 474-80; Fridman et al. J.
Biol Chem. 1994, 269, 30105-8. Kolch et al, (Nature 1991, 349, 426-28) have further
indicated that inhibition of raf expression by antisense RNA blocks cell proliferation
WO 99/32455
2
PCT/US98/26082
in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense
oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the
growth of a variety of human tumor types (Monia et al., Nat Med. 1996, 2, 668-75).
Summary of the Invention
The present invention provides compounds which are inhibitors of the enzyme raf
kinase. Since the enzyme is a downstream effector of p21 ras , the instant inhibitors are
useful in pharmaceutical compositions for human or veterinary use where inhibition
of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or
cancerous cell growth mediated by raf kinase. In particular, the compounds are useful
in the treatment of human or animal, e.g., murine cancer, since the progression of
these cancers is dependent upon the ras protein signal transduction cascade and
therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf
kinase. Accordingly, the compounds of the invention are useful in treating solid
cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid,
bladder or colon, myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g.,
villous colon adenoma).
The present invention, therefore, provides compounds generally described as aryl
ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway.
The invention also provides a method for treating a raf mediated disease state in
humans or mammals. Thus, the invention is directed to compounds and methods for
the treatment of cancerous cell growth mediated by raf kinase comprising
administering a compound of formula I
O
II
A-NH-C-NH-B I
wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or
heteroaryl moiety with up 30 carbon atoms with at least one 5 or 6 member aromatic
structure containing 0-4 members of the group consisting of nitrogen, oxygen and
sulfur. A is a heteroaryl moiety discussed in more detail below.
The aryl and heteroaryl moiety of B may contain separate cyclic structures and can
include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents
WO 99/32455
3
PCT7US98/26082
for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen,
hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those
which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are
discussed more particularly below.
5
Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to
aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of
which is a 5-6 member aromatic ring. One or more of these rings may have 1-4
carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms.
10
Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl,
pyrimidinyl, benzothiozolyl, quinoline, isoquinoline, phthalimidinyl and
combinations thereof, such as diphenyl ether (phenyloxyphenyl), diphenyl thioether
(phenylthiophenyl), diphenyl amine (phenylaminophenyl), phenylpyridinyl ether
15 (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyyridinyl thioether
(pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl),
phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether,
phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether,
pyridinylnaphthyl thioether, and phthalimidylmethylphenyl.
20
Examples of suitable heteroaryl groups include, but are not limited to, 5-12 carbon-
atom aromatic rings or ring systems containing 1-3 rings, at least one of which is
aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can
be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.
25
For example, B can be 2- or 3-fiiryl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-
pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4-
or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-,
5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or-5-yl, 1,2,4-triazol-l-, -3- or-5-yl, 1- or 5-
30 tetrazolyl, l,2,3-oxadiazol-4- or-5-yl, l,2,4-oxadiazol-3- or-5-yl, l,3,4-thiadiazol-2-
or-5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,3,4-thiadiazol-3-
or-5-yl, l,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-
thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-,
5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-
35 benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or
WO 99/32455
PCT/US98/26082
7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-
quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-,
3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally
optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl,
5 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-
thienyl, 4-methyl-2-thienyl, 1 -methyl-3-pyrryl, 1 -m ethyl- 3 -pyrazo ly 1 , 5-methyl-2~
thiazolyl or 5-methyl-l,2,4-thiadiazoi-2-yl.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc., throughout
10 include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched
isomers such as isopropyl, isobutyl, sec-butyl, te/?-butyl, etc.
Suitable aryl groups include, for example, phenyl and 1- and 2-naphthyl.
15 Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, etc. The term
"cycloalkyl", as used herein, refers to cyclic structures with or without alkyl
substituents such that, for example, "C 4 cycloalkyl" includes methyl substituted
cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also
includes saturated heterocycles.
20
Suitable halogens include F, CI, Br, and/or I, from one to persubstitution (i.e., all H
atoms on the group are replaced by halogen atom), being possible, mixed substitution
of halogen atom types also being possible on a given moiety.
25 As indicated above, these ring systems can be unsubstituted or substituted by
substituents such as halogen up to per-halosubstitution. Other suitable substituents for
the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano,
hydroxy and amine. These other substituents, generally referred to as X and X f
herein, include -CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , -SR 5 , -NR 5 R y ,
30 -NR 5 C(0)OR 5 ', -NR 5 C(0)R 5 ', C,-C 10 alkyl, C 2 . 10 -alkenyl, C^o-alkoxy, C 3 -C 10
cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13 heteroaryl, C 4 -C 23 alkheteroaryl,
substituted C r C 10 alkyl, substituted C 2 . 10 -alkenyl, substituted C 2 . 10 -alkoxy, substituted
C 3 -C l0 cycloalkyl, substituted C 4 -C 23 alkheteroaryl and -Y-Ar.
WO 99/32455 PCT/US98/26082
Where a substituent, X or X 1 , is a substituted group, it is preferably substituted by one
or more substituents independently selected from the group consisting of — CN,
-C0 2 R 5 , -C(0)R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 , -N0 2 , -NR 5 C(0)R 5 ',
-NR 5 C(0)OR 5 and halogen up to per-halo substitution.
5
The moieties R 5 and R 5 ' are preferably independently selected from H, C r C 10 alkyl,
C 2 _ 10 -alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23
alkheteroaryl, up to per-halosubstituted C,-C 10 alkyl, up to per-halosubstituted C 2 _ 10 -
alkenyl , up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14
10 aryl and up to per-halosubstituted C 3 -C l3 heteroaryl.
The bridging group Y is preferably -O-, -S-, -N(R 5 )-, -(CH 2 )- m , -C(O)-, -CH(OH)-,
-NR 5 C(0)NR 5 R 5 '-, -NR 5 C(0)-, -C(0)NR 5 -, -(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 5 )-,
-0(CH 2 ) m -, -CHX a , -CX a 2 -, -S-(CH 2 ) m - and -N(R 5 )(CH 2 ) m -, where m = 1-3, and X a is
1 5 halogen.
The moiety Ar is preferably a 5-10 member aromatic structure containing 0-2
members of the group consisting of nitrogen, oxygen and sulfur which is
unsubstituted or substituted by halogen up to per-halo substitution and optionally
20 substituted by Z nJ , wherein nl is 0 to 3.
Each Z substituent is preferably independently selected from the group consisting of
-CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -C(O)- NR 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 ', -NR 5 C(0)OR 5 ',
-C(0)R 5 , -NR 5 C(0)R 5 ', C r C 10 alkyl, C 3 -C ao cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl,
25 C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C, 0
cycloalkyl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl. If Z is a
substituted group, it is substituted by one or more substituents independently selected
from the group consisting of -CN, -C0 2 R 5 , -C(0)NR 5 R 5 , -OR 5 , -SR 5 , -N0 2 , -NR 5 R 5 ',
-NR S C(0)R 5 ' and -NR 5 C(0)OR 5 .
30
The aryl and heteroaryl moieties of B of Formula I are preferably selected from the
group consisting of
WO 99/32455
PCT/US98/26082
R 5 R 5
which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as
defined above and n = 0-3.
5
The aryl and heteroaryl moieties of B are more preferably of the formula:
I-
s
wherein Y is selected from the group consisting of -O-, -S-, -CH 2 -, -SCH 2 -, -CH 2 S-,
-CH(OH)-, -C(O)-, -CX a 2J -CX a H-, -CH 2 0- and -OCH 2 - and X a is halogen.
10
Q is a six member aromatic structure containing 0-2 nitrogen, substituted or
unsubstituted by halogen, up to per-halosubstitution and Q 1 is a mono- or bicyclic
aromatic structure of 3 to 1 0 carbon atoms and 0-4 members of the group consisting
of N, O and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution.
15 X, Z, n and nl are as defined above, and s = 0 or 1.
In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by
halogen, up to per-halosubstitution and Q 1 is selected from the group consisting of
phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and
20 benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, or
WO 99/32455
7
PCT/US98/26082
Y-Q 1 is phthalimidinyl substituted or unsubstituted by halogen up to per-halo
substitution. Z and X are preferably independently selected from the group consisting
of-R 6 , -OR 6 and -NHR 7 , wherein R 6 is hydrogen, C r C 10 -alkyl or C 3 -C 10 -cycloalkyl
and R 7 is preferably selected from the group consisting of hydrogen, C 3 -C 10 -alkyl, C 3 -
C 6 -cycloalkyl and C 6 -C 10 -aryl, wherein R 6 and R 7 can be substituted by halogen or up
to per-halosubstitution.
The heteroaryl moiety A of formula I is preferably selected from the group consisting
wherein R 1 is preferably selected from the group consisting of C 3 -C, 0 alkyl, C 3 -C 10
cycloalkyl, up to per-halosubstituted Ci-C 10 alkyl and up to per-halosubstituted C 3 -C 10
cycloalkyl and R 2 is C 6 -C u aryl, C 3 -C 14 heteroaryl, substituted C 6 -C 14 aryl or
substituted C 3 -C l4 heteroaryl.
Where R 2 is a substituted group, the substituents are preferably independently selected
from the group consisting of halogen, up to per-halosubstitution, and V n , where n =
Each V is preferably independently selected from the group consisting of -CN,
-OC(0)NR 5 R 5 ', -C0 2 R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 ', -C(0)R 5 , - NR 5 C(0)0R 5 ',
-S0 2 R 5 , -SOR 5 , -NR 5 C(0)R 5f , -NO 2 C r C, 0 alkyl, C 3 -C 10 cycloalkyl, C 6 -C t4 aryl, C 3 -C 13
heteroaryl, C 7 -C 24 alkaryl, C 4 -G 24 alkheteroaryl, substituted Cj-C 10 alkyl, substituted
C 3 -C 10 cycloalkyl, substituted C 6 -C 14 aryl, substituted C 3 -C 13 heteroaryl, substituted
C 7 -C 24 alkaryl and substituted C 4 -C 24 alkheteroaryl.
R
R
R
0-3.
If V is a substituted group, it is preferably substituted by one or more substituents
independently selected from the group consisting of halogen, up to per-
halosubstitution, -CN, -C0 2 R 5 , -C(0)R 5 , -C(0 )NR 5 R 5 , -NR 5 R 5 ', -OR 5 , -SR 5 ,
WO 99/32455
8
PCT/US98/26082
-NR 5 C(0)R 5 ',-NR 5 C(0)0R 5 'and -N0 2 .
The substituents R 5 and R 5 * are preferably each independently selected form the group
consisting of H, C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24
alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C r C 10 alkyl, up to per-
halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14 aryl and up to per-
halosubstituted C 3 -C 13 heteroaryl.
R 2 is preferably substituted or unsubstituted phenyl or pyridinyl, where the
substituents for R 2 are selected from the group consisting of halogen, up to per-
halosubstituition and V n \ wherein n = 0-3. Each V 1 is preferably independently
selected from the group consisting of substituted and unsubstituted C r C 6 alkyl, C 3 -C l0
cycloalkyl, C 6 -C 10 aryl, -N0 2 , -NH 2 , -C(0)-C r6 alkyl, -C(0)N-(CV 6 alkyl) 2 , -C(0)NH-
C U6 alkyl, -0-C U6 alkyl, -NHC(0)H, -NHC(0)OH, -N(C,- 6 alkyi)C(0)-C r6 alkyl, -N-
(C r6 alkyl)C(0)-C r6 alkyl, -NHC(0)-C r6 alkyl, -00(0)^-0^4 aryl, -NHC(0)0-
C r6 alkyl, -S(0)-C r6 alkyl and -S0 2 -C r6 alkyl. Where V 1 is a substituted group, it
is preferably substituted by one or more halogen, up to per-halosubstitution.
Most preferably, R 2 is selected from substituted and unsubstituted phenyl or pyridinyl
groups, where the substituents are halogen and W n (n = 0-3).
W is preferably selected from the group consisting of -N0 2 , -C t - 3 alkyl, -NH(0)CH 3 ,
-CF 3 , -OCH 3 , -F, -CI, -NH 2 , -0C(0)NH up to per-halosubstituted phenyl, -S0 2 CH 3 ,
pyridinyl, phenyl, up to per-halosubstituted phenyl and C r C 6 alkyl substituted phenyl.
The invention also relates the compounds within the scope of general formula I
described above. These more particularly include pyrazolyl ureas of the formula
R
NH-C-NH-B
O
II
WO 99/32455
9
PCT/US98/26082
furyl ureas of the formula
O
II
NH-C-NH-B
and thienyl ureas of the formula
wherein R 1 , R 2 and B are as defined above.
The present invention is also directed to pharmaceutically acceptable salts of formula
I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art
10 and include basic salts of inorganic and organic acids, such as hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic
acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid,
oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts
15 include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li +
Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as
well as acid salts of organic bases, including aliphatic and aromatic substituted
ammonium, and quaternary ammonium cations such as those arising from protonation
or peralkylation of triethylamine, iV^-diethylamine, JV;iV-dicyclohexylamine,
20 pyridine, jV^-dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane
(DABCO), l,5-diazabicyclo[43.0]non-5-ene (DBN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU).
A number of the compounds of Formula I possess asymmetric carbons and can
25 therefore exist in racemic and optically active forms. Methods of separation of
enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
WO 99/32455
PCT/US98/26082
The present invention encompasses any isolated racemic or optically active form of
compounds described in Formula I which possess Raf kinase inhibitors.
The compounds of Formula I may be prepared by use of known chemical reactions
5 and procedures, some of which are commercially available. Nevertheless, the
following general preparative methods are presented to aid one of skill in the art in
synthesizing these compounds, with more detailed examples being presented in the
experimental section describing the working examples.
General Preparative Methods
Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et
10 al. Comprehensive Heterocyclic Chemistry*, Permagon Press: Oxford, UK (1984).
March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985)). For
example, as shown in Scheme I, 5-aminopyrazoles substituted at the N-l position with
either aryl or heteroaryl moieties may be synthesized by the reaction of an oc-
cyanoketone (2) with the appropriate aryl- or heteroaryl hydrazine (3, R 2 =aryl or
15 heteroaryl). Cyanoketone 2, in turn, is available from the reaction of acetamidate ion
with an appropriate acyl derivative, such as an ester, an acid halide, or an acid
anhydride. In cases where the R 2 moiety offers suitable anion stabilization, 2-aryl-
and 2-heteroarylfurans may be synthesized from a Mitsunobu reaction of cyanoketone
2 with alcohol 5, followed by base catalyzed cyclization of enol ether 6 to give
20 furylamine 7,
WO 99/32455
11
PCT/US98/26082
CH 3 CN
1 ) base
R
O
t
2) II
R 1> S
NH 2
R
A^CN
2
NH 2
6
7
Scheme I. Selected General Methods for Heterocyclic Amine Synthesis
Substituted anilines may be generated using standard methods (March. Advanced
Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive
Organic Transformations] VCH Publishers: New York (1989)). As shown in Scheme
II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal
catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate,
cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic
Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong
hydride source, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and
Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a
zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist
for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.; John
Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH
Publishers: New York (1989)).
H 2 / catalyst
ArNQ 2
IK]
ArNH 2
\
M(0)
(eg. Fe, Sn, Ca)
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Scheme II Reduction of Nitroaryls to Aryl Amines
Nitroaryls are commonly formed by electrophilic aromatic nitration using HN0 3 , or
an alternative N0 2 + source. Nitro aryls may be further elaborated prior to reduction.
Thus, nitroaryls substituted with
HN0 3
Ar-H ► ArN0 2
potential leaving groups (eg. F, CI, Br, etc.) may undergo substitution reactions on
treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or
phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme
ni).
Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls
As shown in Scheme IV, urea formation may involve reaction of a heteroaryl
isocyanate (12) with an aryl amine (11). The heteroaryl isocyanate may be
synthesized from a heteroaryl amine by treatment with phosgene or a phosgene
equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)
carbonate (triphosgene), or N,N -carbonyldiimidazole (CDI). The isocyanate may
also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an
acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid
derivative 1 6 with an azide source, followed by rearrangement affords the isocyanate.
The corresponding carboxylic acid (17) may also be subjected to Curtius-type
rearrangements using diphenylphosphoryl azide (DPP A) or a similar reagent. A urea
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may also be generated from the reaction of an aryl isocyanate (15) with a heterocyclic
amine.
Het-NH 2 11
COCI 2
t
Het-NCO
12
H 2 N-Ar
HeU K1 J-L.Ar
N N
H H
H 2 N-Ar 14
COCI 2
Het— NH 2
t
OCN-Ar
15
13
\ DPPA
N 3 " /
\ DPPA
O
x
Het^X
O
x
Hef'^OH
O
X^Ar
O
x
HO Ar
16
17
18
19
5 Scheme IV Selected Methods of Urea Formation (Het = heterocycle)
Finally, ureas may be further manipulated using methods familiar to those skilled in
the art. For example, 2-aryl and 2-heteroarylthienyl ureas are available from the
corresponding 2-halothienyl urea through transition metal mediated cross coupling
reactions (exemplified with 2-bromothiophene 25, Scheme V). Thus, reaction of
10 nitrile 20 with an a-thioacetate ester gives 5-substituted-3-amino-2-
thiophenecarboxylate 21 (Ishizaki et al. JP 6025221). Decarboxylation of ester 21
may be achieved by protection of the amine, for example as the tert-butoxy (BOC)
carbamate (22), followed by saponification and treatment with acid. When BOC
protection is used, decarboxylation may be accompanied by deprotection giving the
15 substituted 3-thiopheneammonium salt 23. Alternatively, ammonium salt 23 may be
directly generated through saponification of ester 21 followed by treatment with acid.
Following urea formation as described above, bromination affords penultimate
halothiophene 25. Palladium mediated cross coupling of thiophene 25 with an
appropriate tributyl- or trimethyltin (R 2 = aryl or heteroaryl) then affords the desired 2-
20 aryl- or 2-heteroarylthienyl urea.
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24 25 26
Scheme V
Synthesis and Interconversion of Ureas
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The invention also includes pharmaceutical compositions including a compound of
Formula I 5 and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or
5 spray or vaginally, sublingually, or rectally in dosage unit formulations. The term
'administration by injection' includes intravenous, intramuscular, subcutaneous and
parenteral injections, as well as use of infusion techniques. Dermal administration
may include topical application or transdermal administration. One or more
compounds may be present in association with one or more non-toxic
10 pharmaceutical^ acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method
known to the art for the manufacture of pharmaceutical compositions. Such
compositions may contain one or more agents selected from the group consisting of
15 diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in
order to provide palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutical^ acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for example, inert diluents,
such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium
20 phosphate; granulating and disintegrating agents, for example, com starch, or alginic
acid; and binding agents, for example magnesium stearate, stearic acid or talc. The
tablets may be uncoated or they may be coated by known techniques to delay
disintegration and adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay material such as
25 glyceryl monostearate or glyceryl distearate may be employed. These compounds
may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate,
30 calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive
oil.
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Aqueous suspensions contain the active materials in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such excipients are suspending
agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum
5 acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for
example, lecithin, or condensation products or an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of ethylene oxide with
long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or
condensation products of ethylene oxide with partial esters derived from fatty acids
10 and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for
example polyethylene sorbitan monooleate. The aqueous suspensions may also
contain one or more preservatives, for example ethyl, or n-propyl /?-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one or more
1 5 sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension
by the addition of water provide the active ingredient in admixture with a dispersing
or wetting agent, suspending agent and one or more preservatives. Suitable dispersing
20 or wetting agents and suspending agents are exemplified by those already mentioned
above. Additional excipients, for example, sweetening, flavoring and coloring agents,
may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
25 suspensions which may be formulated by suspending the active ingredients in a
vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a
mineral oil such as liquid paraffin. The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such
as those set forth above, and flavoring agents may be added to provide palatable oral
30 preparations. These compositions may be preserved by the addition of an anti-oxidant
such as ascorbic acid.
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Pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil,
or a mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum acacia or gum
5 tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and
esters or partial esters derived from fatty acids and hexitol anhydrides, for example
sorbitan monooleate, and condensation products of the said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions
may also contain sweetening and flavoring agents.
10
Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a
demulcent, a preservative and flavoring and coloring agents.
15 The compounds may also be administered in the form of suppositories for rectal or
vaginal administration of the drug. These compositions can be prepared by mixing
the drug with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal or vaginal temperature and will therefore melt in
the rectum or vagina to release the drug. Such materials include cocoa butter and
20 polyethylene glycols.
Compounds of the invention may also be administrated transdermally using methods
known to those skilled in the art (see, for example: Chien; ** Transdermal Controlled
Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157
25 3Mar94). For example, a solution or suspension of a compound of Formula I in a
suitable volatile solvent optionally containing penetration enhancing agents can be
combined with additional additives known to those skilled in the art, such as matrix
materials and bacteriocides. After sterilization, the resulting mixture can be
formulated following known procedures into dosage forms. In addition, on treatment
30 with emulsifying agents and water, a solution or suspension of a compound of
Formula I may be formulated into a lotion or salve.
WO 99/32455 18 PCT/US98/26082
Suitable solvents for processing transdermal delivery systems are known to those
skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol,
lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate,
polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane
5 or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform,
trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include
mixtures of one or more materials selected from lower alcohols, lower ketones, lower
carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
10 Suitable penetration enhancing materials for transdermal delivery system are known
to those skilled in the art, and include, for example, monohydroxy or polyhydroxy
alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated
C 8 — C lg fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated
C 8 -C 18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to
15 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl
tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic
acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic
acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate,
diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional
20 penetration enhancing materials include phosphatidyl derivatives such as lecithin or
cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as
dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration
enhancing formulations may also include mixtures of one or more materials selected
from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -C 18 fatty
25 alcohols, saturated or unsaturated C 8 -C 18 fatty acids, saturated or unsaturated fatty
esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids
with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones,
ureas and their derivatives, and ethers.
30 Suitable binding materials for transdermal delivery systems are known to those skilled
in the art and include polyacrylates, silicones, polyurethanes, block polymers,
styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers,
derivatized polyethylenes, and silicates may also be used as matrix components.
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Additional additives, such as viscous resins or oils may be added to increase the
viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral
5 dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily dosage for administration by injection, including intravenous, intramuscular,
subcutaneous and parenteral injections, and use of infusion techniques will preferably
be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen
will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal
10 dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily topical dosage regime will preferably be from 0.1 to 200 mg administered
between one to four times daily. The transdermal concentration will preferably be that
required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation
dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
15
It will be appreciated by those skilled in the art that the particular method of
administration will depend on a variety of factors, all of which are considered
routinely when administering therapeutics. It will also be understood, however, that
the specific dose level for any given patient will depend upon a variety of factors,
20 including, the activity of the specific compound employed, the age of the patient, the
body weight of the patient, the general health of the patient, the gender of the patient,
the diet of the patient, time of administration, route of administration, rate of
excretion, drug combinations, and the severity of the condition undergoing therapy.
25 It will be further appreciated by one skilled in the art that the optimal course of
treatment, ie., the mode of treatment and the daily number of doses of a compound of
Formula I or a pharmaceutically acceptable salt thereof given for a defined number of
days, can be ascertained by those skilled in the art using conventional treatment tests.
30 It will be understood, however, that the specific dose level for any particular patient
will depend upon a variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of administration,
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route of administration, and rate of excretion, drug combination and the severity of the
condition undergoing therapy.
The entire disclosure of all applications, patents and publications cited above and
5 below are hereby incorporated by reference, including provisional application
[Attorney Docket Bayer 9V1], filed on December 22, 1997 as SN 08/996,181 and
converted on December 22, 1998.
The compounds are producible from known compounds (or from starting materials
10 which, in turn, are producible from known compounds), e.g., through the general
preparative methods shown below. The activity of a given compound to inhibit raf
kinase can be routinely assayed, e.g., according to procedures disclosed below. The
following examples are for illustrative purposes only and are not intended, nor should
they be construde to limit the invention in any way.
15
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
20 introduced into reaction vessels through rubber septa. Unless otherwise stated, the
term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator
at approximately 15 mmHg.
All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise
25 indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification. Thin-
layer chromatography (TLC) was performed on Whatman® pre-coated glass-backed
silica gel 60A F-254 250 nm plates. Visualization of plates was effected by one or
30 more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine
vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in
ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution
followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of
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2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash
chromatography) was performed using 230-400 mesh EM Science® silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus
or a Mettler FP66 automated melting point apparatus and are uncorrected. Proton ( ! H)
nuclear magnetic resonance (NMR) spectra were measured with a General Electric
GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual
protonated solvent (CHC1 3 8 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. Carbon
( I3 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz)
spectrometer with solvent (CDC1 3 8 77.0; MeOD-d 3 ; 8 49.0; DMSO-d 6 8 39.5) as
standard. Low resolution mass spectra (MS) and high resolution mass spectra
(HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom
bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were
obtained with a Hewlett Packard 5989A mass spectrometer equipped with a
Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion
source was maintained at 250 °C. Electron impact ionization was performed with
electron energy of 70 eV and a trap current of 300 |iA. Liquid-cesium secondary ion
mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained
using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS)
were obtained using a Hewlett Packard MS-Engine (59 89 A) with methane as the
reagent gas (lxlO* 4 torr to 2.5X10" 4 ton). The direct insertion desorption chemical
ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec
and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra
were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra
(HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a
quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan
LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned
from 120-800 amu using a variable ion time according to the number of ions in the
source. Gas chromatography - ion selective mass spectra (GC-MS) were obtained
with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl
silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass
Selective Detector (ionization energy 70 eV).
WO 99/32455 22 PCT/US98/26082
Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. All
compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistant with assigned structures.
5
List of Abbreviations and Acronyms:
AcOH acetic acid
anh anhydrous
BOC ter/-butoxycarbonyl
1 0 cone concentrated
dec decomposition
DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
DMF N, 7V-dimethylformamide
DMSO dimethylsulfoxide
15 DPP A diphenylphosphoryl azide
EtOAc ethyl acetate
EtOH ethanol(100%)
Et 2 0 diethyl ether
Et 3 N triethylamine
20 /w-CPBA 3-chloroperoxybenzoic acid
MeOH methanol
pet. ether petroleum ether (boiling range 30-60 °C)
THF tetrahydrofuran
TFA trifluoroacetic acid
25 Tf trifluoromethanesulfonyl
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A. General Methods for Synthesis of Heterocyclic Amines
Al. General Procedure for the Preparation of TV'-Aryl-S-aminopyrazoles
A r/ -(4-MethoxyphenyI)-5-amino-3-^rT-butylpyrazoIe: A mixture of 4-
methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5
g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h,
cooled to room temp., and poured into a mixture of E^O (100 mL) and a 10% Na^C^
solution (100 mL). The organic layer was washed with a saturated NaCl solution,
dried (MgS0 4 ) and concentrated under reduced pressure. The solid residue was
washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25g): *H-
NMR (DMSO-d 6 ) 5 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d,
7=8 Hz, 2H); 7.42 (d, 7=8 Hz, 2H).
General Method for the Mitsunobu-Based Synthesis of 2-Aryl-3-aminofurans
Step 1. 4,4-Dimethyl-3-(4-pyridinylmethoxy)-2-pentenenitrae: A solution of
triphenylphosphine (2.93 g, 11.2 mmol) in anh THF (50 mL) was treated with diethyl
azodicarboxylate (1.95 g, 11.2 mmol) and 4-pyridinylmethanol (1.22 g, 11.2 mmol),
then stirred for 15 min. The resulting white slurry was treated with 4,4-dimethyl-3-
oxopentanenitrile (1.00 g, 7.99 mmol), then stirred for 15 min. The reaction mixture
was concentrated under reduced pressure. The residue was purified by column
chromatography (30% EtO Ac/70% hexane) to give the desired nitrile as a yellow
solid (1.83 g, 76%): TLC (20% EtOAc/80% hexane) R^O.13; 'H-NMR (CDC1 3 ) 5
1.13 (s, 9H), 4.60 (s, 1H), 5.51 (s, 2H), 7.27 (d, 7=5.88 Hz, 2H), 8.60 (d, 7=6.25 Hz,
2H); I3 C-NMR (CDC1 3 ) 5 27.9 (3C), 38.2, 67.5, 70.8, 117.6, 121.2 (2C), 144.5, 149.9
(2C), 180.7; CI-MS m/z (rel abundance) 217 ((M+H) + , 100%).
MeO
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Step 2. 3-Amino-2-(4-pyridinyl)-5-ter*-butyIfuran: A solution of 4,4-dimethyl-3-
(4-pyridinylmethoxy)-2-pentenenitrile (1.55 g, 7.14 mmol) in anh DMSO (75 mL)
was treated with potassium /erf-butoxide (0.88 g, 7.86 mmol) and stirred at room
5 temp for 10 min. The resulting mixture was treated with EtOAc (300 mL), then
sequentially washed with water (2 x 200 mL) and a saturated NaCl solution (100 mL).
Combined aqueous phases were back-extracted with EtOAc (100 mL). The combined
organic phases were dried (Na^OJ and concentrated under reduced pressure. The
residue was purified by column chromatography (gradient from 30% EtO Ac/70%
10 hexane to 100% EtOAc) to give the desired product as an orange oil (0.88 g, 57%):
TLC (40% EtOAc/60% hexane) 0.09; 'H-NMR (CDC1 3 ) 8 1.28 (s, 9H) 5 3.65 (br s,
2H), 5.79 (s, 1H), 7.30 (d, J=6.25 Hz, 2H), 8.47 (d, 7=6.25 Hz, 2H); EI-MS m/z (rel
abundance) 216 (M + , 30%).
1A3. Synthesis 3-Amino-5-alkyIthiophenes from 7V-BOC 3-Amino-5-alkyl-2-
thiopiieiiecai boxylate esters
Step 1. Methyl 3-(^rr-Butoxycarbonylamino)-5-^rr-butyI-2-thiophenecarboxy-
late: To a solution of methyl 3-amino-5-^-butyl-2-thiophenecarboxylate (150 g,
20 0.70 mol) in pyridine (2.8 L) at 5 °C was added di-ter*-butyl dicarbonate (171.08 g,
0.78 mol, 1.1 equiv) and MA^-dimethylaiiiinopyridine (86 g, 0.70 mol, 1.00 equiv) and
the resulting mixture was stirred at room temp for 7 d. The resulting dark solution
was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately
20 °C. The resulting red solids were dissolved in CH 2 C1 2 (3 L) and sequentially
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washed with a 1 M H 3 P0 4 solution (2 x 750 mL), a saturated NaHC0 3 solution (800
mL) and a saturated NaCl solution (2 x 800 mL), dried (NajSO^ and concentrated
under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2
L) by warming to 49 °C, then treated with water (500 mL) to afford the desired
product as an off-white solid (163 g, 74%): l H-NMR (CDC1 3 ) 5 1.38 (s, 9H), 1.51 (s,
9H), 3.84 (s, 3H), 7.68 (s, 1H), 9.35 (br s, 1H); FAB-MS m/z (rel abundance) 314
((M+H) + , 45%).
Step 2. 3-(^r^-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic Acid:
To a solution of methyl 3-(re^-butoxycarbonylamino)-5-rerr-butyl-2-
thiophenecarboxylate (90.0 g, 0.287 mol) in THF (630 mL) and MeOH (630 mL) was
added a solution of NaOH (42.5 g, 1.06 mL) in water (630 mL). The resulting
mixture was heated at 60 °C for 2 h, concentrated to approximately 700 mL under
reduced pressure, and cooled to 0 °C. The pH was adjusted to approximately 7 with a
1.0 N HC1 solution (approximately 1 L) while maintaining the internal temperature at
approximately 0 °C. The resulting mixture was treated with EtOAc (4 L). The pH
was adjusted to approximately 2 with a 1.0 N HC1 solution (500 mL). The organic
phase was washed with a saturated NaCl solution (4 x 1.5 L), dried (Na^OJ, and
concentrated to approximately 200 mL under reduced pressure. The residue was
treated with hexane (1 L) to form a light pink (41.6 g). Resubmission of the mother
liquor to the concentration-precipitation protocol afforded additional product (38.4 g,
93% total yield): 'H-NMR (CDC1 3 ) 5 1.94 (s, 9H), 1.54 (s, 9H), 7.73 (s, 1H), 9.19 (br
s, 1H); FAB-MS m/z (rel abundance) 300 ((M+H) + , 50%).
NH 3 + CI
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Step 3. 5-te/*4Jutyl-3-thiopheneammonium Chloride: A solution of 3-(tert-
butoxycarbonylamino)-5-rer/-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in
dioxane (20 mL) was treated with an HC1 solution (4.0 M in dioxane, 12.5 mL, 0.050
mol, 5.0 equiv), and the resulting mixture was heated at 80 °C for 2 h. The resulting
5 cloudy solution was allowed to cool to room temp forming some precipitate. The
slurry was diluted with EtOAc (50 mL) and cooled to -20 °C. The resulting solids
were collected and dried overnight under reduced pressure to give the desired salt as
an off-white solid (1.72 g, 90%): 'H-NMR (DMSO-d 6 ) 8 1.31 (s, 9H), 6.84 (d, J=1.48
Hz, 1H), 7.31 (d, J=1.47 Hz, 1H), 10.27 (br s, 3H).
10
B. Genera] Methods for Synthesis of Substituted Anilines
Bl. General Method for Substituted Aniline Synthesis via Nucleophilic
Aromatic Substitution using a Halopyridine
15 3-(4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles)
in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles)
followed by K 2 C0 3 (16.7 g, 121 mmoles). The reaction mixture was stirred at room
temp, for 1.5 h, then diluted with EtO Ac (100 mL) and water (lOOmL). The aqueous
layer was back-extracted with EtO Ac (2 x 100 mL). The combined organic layers
20 were washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ), and
concentrated under reduced pressure. The residue was filtered through a pad of silica
(gradient from 50% EtO Ac/50% hexane to 70% EtO Ac/30% hexane) and the resulting
material was triturated with a E^O/hexane solution to afford the desired product (4.6
g, 66%): TLC (100 % ethyl acetate) R^O.29; l H-NMR (DMSO-d 6 ) 8 5.41 (s, 2H),
25 6.64-6.74 (m, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d 5 J=4.8, 2H).
C. General Methods of Urea Formation
CI a. Reaction of a Heterocyclic Amine with an Aryl Isocyanate
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MeO
A41 -(4-Metho^phenyl)-3-*^
To a stirring solution of l-(4-methoxyphenyl)-3-^rr-butyl-5-aminopyrazole (0.342 g,
1.39 mmol) in anh toluene (9 mL) was added 2,3-dichlorophenyl isocyanate (0.276
mL, 2.09 mmol). The solution was sealed and stirred in the dark for 96 h at 60 °C.
After this time, the reaction mixture was diluted with EtOAc (200 mL). The resulting
mixture was sequentially washed with a 1 M HC1 solution (2 x 125 mL) and a
saturated NaCl solution (50 mL), dried (MgSOJ, and concentrated under reduced
pressure. The residue was purified by column chromatography (20% EtOAc/80%
hexane) to give the product as a white solid (0.335 g, 56%): TLC (20% EtOAc/80%
hexane) 0.22; 'H NMR (DMSOd 6 ) 8 1.24 (s, 9H), 3.79 (s, 3H), 6.33 (s, 1H), 7.05
(d, J=9 Hz, 2H), 7.28 (m, 2H), 7.38 (d, J=9 Hz, 2H), 8.05 (dd, J=3, 6 Hz, 1H), 8.75
(s, 1H), 9.12 (s, 1H); FAB-MS m/z433 ((M+H) + ).
Clb. Reaction of a Heterocyclic Amine with an Aryl Isocyanate
jV-(2-(4-Pyridinyl)-5-^-butyI-3-furyl)-A^ , -(2,3-dichlorophenyI)urea: A solution
of 3-amino-2-(4-pyridinyl)-5-^-butylfuran (Method A2; 0.10 g, 0.46 mmol) and
2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH 2 C1 2 was stirred at room
temp, for 2 h, then was treated with 2-(dimethylamino)ethylamine (0.081 g, 0.92
mmol) and stirred for an additional 30 min. The resulting mixture was diluted with
EtOAc (50 mL), then was sequentially washed with a 1 N HC1 solution (50 mL), a
saturated NaHC0 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried
(NajSOJ, and concentrated under reduced pressure. The residue was purified using
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column chromatography (gradient from 10% EtO Ac/90% hexane to 40% EtO Ac/60%
hexane) to give the desired compound as a white solid (0.12 g, 63%): mp 195-198 °C;
TLC (60% EtO Ac/40% hexane ) R^O.47; 'H NMR (DMSO-d 6 ) $ 1.30 (s, 9H); 6.63 (s,
1H); 7.30-7.32 (m, 2H), 7.58 (dm, .7=6.62 Hz, 2H), 8.16 (dd, 7=2.57, 6.99 Hz, 1H),
8.60 (dm, .7=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13 C NMR (DMSO-d 6 ) 8 28.5
(3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5,
137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 ((M+H) + , 15%), 406
((M+H+2) + , 8%).
Clc. Reaction of a Heterocyclic Amine with an Isocyanate
^-(S-rcrt-Butyl-S-thienyO-A^Hi^-dichlorophenyOurea: Pyridine (0.163 mL, 2.02
mmol) was added to a slurry of 5-ier?-butylthiopheneammonium chloride (Method
A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL, 2.02 mmol) in
CH 2 C1 2 (10 mL) to clarify the mixture and the resulting solution was stirred at room
temp, overnight. The reaction mixture was then concentrated under reduced pressure
and the residue was separated between EtO Ac (15 mL) and water (15 mL). The
organic layer was sequentially washed with a saturated NaHC0 3 solution (1 5 mL), a
IN HC1 solution (15 mL) and a saturated NaCl solution (15 mL), dried (NajSO,,), and
concentrated under reduced pressure. A portion of the residue was by preparative
HPLC (C-18 column; 60% acetonitrile/40% water/0.05% TFA) to give the desired
urea (0.180 g, 34%): mp 169-170 °C; TLC (20% EtOAc/80% hexane) R^O.57; 'H-
NMR (DMSO-d 6 ) S 1.31 (s, 9H), 6.79 (s, 1H), 7.03 (s, 1H), 7.24-7.33 (m, 2H), 8.16
(dd, .7=1.84, 7.72 Hz, 1H), 8.35 (s, 1H), 9.60 (s, 1H); I3 C-NMR (DMSO-d 6 ) 8 31.9
(3C), 34.0, 103.4, 116.1, 119.3, 120.0, 123.4, 128.1, 131.6, 135.6, 138.1, 151.7, 155.2;
FAB-MS m/z (rel abundance) 343 ((M+H) + , 83%), 345 ((M+H+2)\ 56%), 347
((M+H+4) + , 12%).
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C2. Reaction of Substituted Aniline with A^A^-Carbonyldiimidazole Followed by
Reaction with a Heterocyclic Amine
iV-(l-Phenyl-3-^it-butyl-5-pyrazolyl)-A r, -(4-(4-pyridinylmethyl)phenyI)urea: A
5 solution of 4-(4-pyridinylmethyI)aniline (0.25 g, 13 8 mmol) and A^iV"-
carbonyldiimidazole (0.23 g, 1.42 mmol) in CH 2 C1 2 11 mL) at room temp, was stirred
for 2 h, then treated with 5-amino-l-phenyl-3-terf-butyl-5-pyrazole (0.30 g, 1.38
mmol) and the resulting mixture was stirred at 50 °C overnight. The reaction mixture
was diluted with EtOAc (25 mL), then sequentially washed with water (30 mL) and a
10 saturated NaCl solution (30 mL), dried (MgS0 4 ), and concentrated under reduced
pressure. The residue was purified by column chromatography (gradient from 100%
CH 2 C1 2 to 30% acetone/70% CH 2 C1 2 ) and the resulting material was recrystallized
(EtOAc/Et 2 0) to give the desired product complexed with 0.25 equiv H 2 0 (0.30 g):
TLC (60% acetone/40% CH 2 C1 2 ) 0.56; 'H-NMR (DMSOd 6 ) 8 1.25 (s, 9H); 3.86 (s,
15 2H), 6.34 (s, 1H), 7.11 (d, J=8.82 Hz, 2H), 7.19 (dm, J=6.25 Hz, 2H), 7.31 (d, 7=1.84
Hz, 2H), 7.35-7.51 (m, 5 H), 8.34 (s, 1H), 8.42 (dm, J=5.98 Hz, 2H), 8.95 (s, 1H);
FAB-MS m/z (rel abundance) 426 ((M+H) + , 100%).
D. Intercon version of Ureas
20 Dl. General Method for Electrophylic Halogenation of Aryl Ureas
^-(Z-Bromo-S-re/t-butyl-S-thienyl)-^ -(2-3-dichlorophenyI)urea: To a slurry of A^-
(5-^-butyl-3-thienyl)-^'-(2,3-dichlorophenyl)urea (Method Clc; 3.00 g, 8.74 mmol)
in CHC1 3 (200 mL) at room temp was slowly added a solution of Br 2 (0.46 mL, 1 .7
25 mmol) in CHC1 3 (150 mL) via addition funnel over 2.5 h, causing the reaction mixture
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to become homogeneous. Stirring was continued 20 min after which TLC analysis
indicated complete reaction. The reaction mixture was concentrated under reduced
pressure, and the residue triturated (Et 2 OZhexane) and the resulting solids were washed
(hexane) to give the brominated product as a pink powder (3.45 g, 93%): mp 180-183
5 °C; TLC (10% EtOAc/90% hexane) 0.68; *H NMR (DMSO-d 6 ) 5 1.28 (s, 9H),
7.27-7.31 (m, 2H), 7.33 (s, 1H), 8.11 (dd, J=3.3, 6.6 Hz, 1H), 8.95 (s, 1H), 9.12 (s,
1H); I3 C NMR (DMSO-d 6 ) 8 31.5 (3C), 34.7, 91.1, 117.9, 120.1, 120.5, 123.8, 128.0,
131.6, 135.5, 137.9, 151.6, 155.3; FAB-MS m/z (rel abundance) 421 ((M+H) + , 7%),
423 (M+2+H) + , 10%).
10
D2. General Method for Metal-Mediated Cross-Coupling Reactions with Halogen-
Substituted Ureas
^-(Z-Phenyl-S-^rr-butyl-S-thienyl)-^ -(2,3-dichlorophenyl)urea: To a solution of
15 A r -(3-(2-bromo-5-re^butylthienyl)-A? r, -(2,3-dichlorophenyl)urea (0.50 g, 1.18 mmol)
and phenyltrimethyltin (0.21 mL, 1.18 mmol) in DMF (15 mL) was added
Pd(PPh 3 ) 2 Cl 2 (0.082 g, 0.12 mmol), and the resulting suspension was heated at 80 °C
overnight. The reaction mixture was diluted with EtOAc (50 mL) and water (50 mL),
and the organic layer sequentially washed with water (3 x 50 mL) and a saturated
20 NaCl solution (50 mL), then dried (NajSOJ and concentrated under reduced pressure.
The residue was purified by MPLC (Biotage®; gradient from 100% hexane to 5%
EtOAc/95% hexane) followed by preparative HPLC (C-18 column; 70% CH 3 CN/30%
water/0.05% TFA). The HPLC fractions were concentrated under reduced pressure
and the resulting aqueous mixture was extracted with EtOAc (2 x 50 mL). The
25 combined organic layers were dried (Na^OJ and concentrated under reduced
pressure to give a gummy semi-solid, which was triturated with hexane to afford the
desired product as a white solid (0.050 g, 10%): mp 171-173 °C; TLC (5%
EtOAc/95% hexane) R^O.25; 'H NMR (CDC1 3 ) 5 1.42 (s, 9H), 6.48 (br s, 1H), 7.01 (s,
1H), 7.10-7.18 (m, 2H), 7.26-7.30 (m, 1H), 7.36 (app t, J=7.72 Hz, 2H), 7.39 (br s,
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1H), 7.50 (dm, J=6.99 Hz, 2H), 7.16 (dd, 7=2.20, 7.72 Hz, 1H); I3 C NMR (CDC1 3 ) 5
32.1 (3C), 34.8, 118.4, 118.8, 120.7, 121.1, 124.2, 127.7, 127.9, 128.2 (2C), 128.5,
129.0 (2C), 132.4, 132.5, 136.9, 153.1, 156.3; FAB-MS m/z (rel abundance) 419
((M+H) + , 6%), 421 ((M+H+2) + , 4%).
5
D3. General Methods of Reduction of Nitro-Containing Aryl Ureas
NH 2
A L (l-(3-Aminophenyl)-3-^r/-butyl-5-pyrazolyl)-7V-(4-(4-
pyridinylthio)phenyl)urea: A solution of N-{\ -(3-nitrophenyl)-3-ter*-butyl-5-
10 pyrazolyl]-7V r -(4-(4-pyridinylthio)phenyl)urea (Prepared in methods analogous to
those described in Al and CI a; 0.310 g, 0.635 mmol) in acetic acid (20 mL) was
placed under an atmosphere of Ar using a vacuum-degassed and argon-purge
protocol. To this was added water (0.2 mL) followed by iron powder (325 mesh;
0.354 g, 6.35 mmol). The reaction mixture was stirred vigorously under argon at
1 5 room temp, for 1 8 h, at which time TLC indicated the absence of starting material.
The reaction mixture was filtered and the solids were washed copiously with water
(300 mL). The orange solution was then brought to pH 4.5 by addition of NaOH
pellets (a white precipitate forms). The resulting suspension was extracted with Et 2 0
(3 x 250 mL), and the combined organic layers were washed with a saturated NaHC0 3
20 solution (2 x 300 mL) until foaming ceased. The resulting solution was dried
(MgS0 4 ) and concentrated under reduced pressure. The resulting white solid was
purified by column chromatography (gradient from 30% acetone/70% CH 2 C1 2 to 50%
acetone/50% CH 2 C1 2 ) to give the product as a white solid (0.165 g, 57%): TLC (50%
acetone/50% CH 2 C1 2 ) R, 0.50; ! H NMR (DMSO-d 6 ) 8 1.24 (s, 9H), 5.40 (br s, 2H),
25 6.34 (s, 1H), 6.57 (d, 7=8 Hz, 2H), 6.67 (s, 1H), 6.94 (d, 7=6 Hz, 2H), 7.12 (app t,
7=8 Hz, 1H), 7.47 (d, 7=9 Hz, 2H), 7.57 (d, 7=9 Hz, 2H), 8.31 (d, 7=6 Hz, 2H), 8.43
(s, 1H), 9.39 (s, 1H); FAB-MS m/z 459 ((M+H) + ).
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D4. General Methods of Acylation of Amine-Containing Aryl Ureas
10
15
A r -(l-(3-AcetamidophenyI)-3-^rNbutyl-5--pyrazolyI)-A^ f -(4-phenoxyphenyl)urea:
To a solution of A r -(l-(3-aminophenyl)-3-rerr-butyl-5-pyrazolyl)-A''-(4-
phenoxyphenyl)urea (prepared using methods analogous to those described in Al,
Cla and D3; 0.154 g, 0.349 mmol) in CH 2 C1 2 (10 mL) was added pyridine (0.05 mL)
followed by acetyl chloride (0.030 mL, 0.417 mmol). The reaction mixture was
stirred under argon at room temp, for 3 h, at which time TLC analysis indicated the
absence of starting material. The reaction mixture was diluted with CH 2 C1 2 (20 mL),
then the resulting solution was sequentially washed with water (30 mL) and a
saturated NaCl solution (30 mL), dried (MgS0 4 ) and concentrated under reduced
pressure. The resulting residue was purified by column chromatography (gradient
from 5% EtOAc/95% hexane to 75% EtOAc/25% hexane) to give the product as a
white solid (0.049 g, 30%): TLC (70% EtOAc/30% hexane) 0.32; ! H NMR
(DMSO-d 6 ) 5 1.26 (s, 9H), 2.05 (s, 3H), 6.35 (s, 1H), 6.92-6.97 (m, 4H), 7.05-7.18
(m, 2H), 7.32-7.45 (m, 5H), 7.64-7.73 (m, 2H), 8.38 (s, 1H), 9.00 (s, 1H), 10.16 (s,
1H); FAB-MS m/z 484 ((M+H) + ).
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The following compounds have been synthesized according to the General Methods
listed above:
Table 1.
2-Substitated-5-ter*-butylpyrazolyl Ureas
Entry
R 1
R 2
mp
(°C)
TLC
Solvent
System
Mass
Spec.
[Source]
Synth.
Method
1
0.42
20%
EtOAc/
80%
hexane
403
(M+H)+
[FAB]
Al,
Cla
V ^ — NH-
0.50
67%
EtOAc/
33%
hexane
418
(M+H)+
[FAB]
Al,
Cla,
D3
Me
0.27
20%
EtOAc/
80%
hexane
417
(M+H)+
[FAB]
Al,
Cla
CI CI
0.47
20%
EtOAc/
80%
hexane
404
(M+H)+
[FAB]
Al,
Cla
0.30
33%
EtOAc/
67%
hexane
473
(M+H)+
[FAB]
Al,
Cla
0.27
100%
EtOAc
421
(M+H)+
fFAB]
Al,
Cla
CI CI
0.50
20%
EtOAc/
437
(M+H)+
Al,
Cla
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80%
hexane
[FAB]
8
/ \
CI CI
0.60
50%
EtOAc/
50%
hexane
481
(M+H)+
[FAB]
Al,
Cla
/ \
-NO-
0.37
20%
EtOAc/
80%
hexane
448
(M+H)+
[FAB]
Al,
Cla
10
OMe
0.35
20%
EtOAc/
80%
hexane
433
(M+H)+
[FAB]
Al,
Cla
11
CI CI
0.40
20%
EtOAc/
80%
hexane
471
(M+H)+
[FAB]
Al,
Cla
12
/ \
•OMe
0.22
20%
EtOAc/
80%
hexane
433
(M+H)+
[FAB]
Al,
Cla
13
CI CI
0.51
20%
EtOAc/
80%
hexane
445
(M+H)+
[FAB]
Al,
Cla
14
15
16
NH-
CI CI
N0 2
<5
ci ci
0.39
50%
EtOAc/
50%
hexane
0.31
30%
EtOAc/
70%
hexane
195
200
418
(M+H)+
[FAB]
Al,
Cla,
D3
448
(M+H)+
[FAB]
Al,
Cla
437
(M+H)+
TFAB]
Al,
Cla
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17
97-
100
403
(M+H)+
[FAB]
Al, 1
Cla
18
\=/
\=/
F
84-
85
371
(M+H)+
TFAB]
Al,
Cla
19
F
156
159
353
(M+H)+
TFAB1
Al,
Cla
20
\— /
CN
168
169
360
(M+H)+
fFAB]
Al, 1
Cla
21
131
135
380
(M+H)+
rcii
Al,
Cla
22
NH
Me
0.31
70%
EtOAc/
30%
X 1 wACUlV
484
(M+H)+
[FAB]
Al,
Cla,
D3,D4
23
NH 2
0.14
50%
EtOAc/
50%
442
(M+H)+
[FAB]
Al,
Cla,
D3
24
N0 2
0.19
30%
EtOAc/
70%
hexane
472
(M+H)+
[FAB]
Al,
Cla
25
-o
0.56
60%
acetone
/ 40%
CH2C1
2
426
(M+H)+
[FAB]
A1,C2
26
0.34
10%
MeOH/
90%
CH2C1
427
(M+H)+
[FAB]
A1.C2
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2
27
CI
-P
CI
0.44
40%
acetone
/ 60%
CH2C1
2
494
(M+H)+
[FAB]
28
0.44
40%
acetone
/ 60%
CH2C1
2
444
(M+H)+
[FAB]
A1.C2
29
-p
Me
0.46
40%
acetone
/ 60%
CH2C1
2
440
(M+H)+
[FAB]
A1.C2
30
-<-?
F
0.48
40%
acetone
/ 60%
CH2C1
2
444
(M+H)+
[FAB]
A1.C2
31
— {~v4f°
\=r/ Me
0.34
40%
acetone
/ 60%
CH2C1
2
504
(M+H)+
A1.C2
32
-OK>
0.47
40%
acetone
/ 60%
CH2C1
2
471
(M+H)+
[FAB]
A1.C2
33
OMe
0.51
60%
acetone
/ 40%
CH2C1
2
456
(M+H)+
[FAB]
A1.C2
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34
NH 2
0.50
50%
acetone
/ 50%
CH2C1
2
441
(M+H)+
[FAB]
Al, C2,
D3
35
N0 2
0.43
30%
acetone
/ 70%
CH2C1
2
471
(M+H)+
[FAB]
A1.C2
36
NH 2
-O-'-O
0.50
50%
acetone
/ 50%
CH2C1
2
459
(M+H)+
[FAB]
Al, C2,
D3
37
NO z
-O-O
0.47
30%
acetone
/ 70%
CH2C1
2
489
(M+H)+
[FAB]
A1,C2
38
Cl KH
Cl Cl
0.47
50%
EtOAc/
50%
hexane
620
(M+H)+
[FAB]
Al, C2
39
OH
Cl Cl
0.34
50%
EtOAc/
50%
hexane
433
(M+H)+
[FAB]
A1,C2
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Table 2. Additional Ureas
mp
TLC
Solvent
Mass
Synth.
(°C)
System
Spec.
Method
195-
0.47
60%
404
A2,
198
EtOAc/
(M+H)+
Clb
40%
[FAB]
171-
0.25
5%
419
A3,
173
EtOAc/
(M+H)+
Clc,
95%
[FAB]
D1,D2
hexane
BIOLOGICAL EXAMPLES
In Vitro raf Kinase Assay :
In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCl, pH 8.2
containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20
|iiL) is mixed with water (5 jiL) or with compounds diluted with distilled water from
10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is
initiated by adding 25 ^iL [y- 33 P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH
7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCl 2 . The reaction mixtures are
incubated at 32 °C, usually for 22 min. Incorporation of 33 P into protein is assayed by
harvesting the reaction onto phosphocellulose mats, washing away free counts with a
1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation
counting. For high throughput screening, 10 jiM ATP and 0.4 pM MEK are used. In
some experiments, the kinase reaction is stopped by adding an equal amount of
Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by
electrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an
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imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging
Analyzer System.
All compounds exemplified displayed IC 50 s of between 1 nM and 10 \xM.
5
Cellular Assay :
For in vitro growth assay, human tumor cell lines, including but not limited to
HCT116 and DLD-1, containing mutated K-ras genes are used in standard
proliferation assays for anchorage dependent growth on plastic or anchorage
1 0 independent growth in soft agar. Human tumor cell lines were obtained from ATCC
(Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine
serum and 200 mM glutamine. Cell culture media and additives are obtained from
Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences,
Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X
15 10 3 cells are seeded into 96-well tissue culture plates and allowed to attach overnight
at 37 °C in a 5% C0 2 incubator. Compounds are titrated in media in dilution series
and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a
feeding of fresh compound containing media on day three. Proliferation is monitored
by measuring metabolic activity with standard XTT colorimetric assay (Boehringer
20 Mannheim) measured by standard ELISA plate reader at OD 490/560, or by
measuring 3 H-thymidine incorporation into DNA following an 8 h culture with 1 \iCu
3 H-thymidine s harvesting the cells onto glass fiber mats using a cell harvester and
measuring 3 H-thymidine incorporation by liquid scintillant counting.
25 For anchorage independent cell growth, cells are plated at 1 x 10 3 to 3 x 10 3 in 0.4%
Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing
only 0.64% agar in RPMI complete media in 24-well tissue culture plates. Complete
media plus dilution series of compounds are added to wells and incubated at 37 °C in
a 5% C0 2 incubator for 10-14 days with repeated feedings of fresh media containing
30 compound at 3-4 day intervals. Colony formation is monitored and total cell mass,
average colony size and number of colonies are quantitated using image capture
technology and image analysis software (Image Pro Plus, media Cybernetics).
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These assays establish that the compounds of formula I are active to inhibit raf kinase
activity and to inhibit oncogenic cell growth.
5 Tn Vivo Assay :
An in vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid
cancers) mediated by raf kinase can be performed as follows:
CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1 x 10 6
10 cells with human colon adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o.
at 10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is
between 50-100 mg. Animals are dosed for 14 consecutive days once a day; tumor
size was monitored with calipers twice a week.
15 The inhibitory effect of the compounds on raf kinase and therefore on tumors (e.g.,
solid cancers) mediated by raf kinase can further be demonstrated in vivo according to
the technique of Monia et al. (Nat. Med. 1996, 2, 668-75).
20 The preceding examples can be repeated with similar success by substituting the
generically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential
25 characteristics of this invention and, without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
various usages and conditions.
30
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PCT/US98/26082
5
WHAT IS CLAIMED IS:
1 . A compound of formula I and pharmaceutically acceptable salts thereof
O
II
A-NH-C-NH-B I
10 wherein A is a heteroaryl selected from the group consisting of
and
y v
R R
wherein R 1 is selected from the group consisting of C 3 -C 10 alkyl, C 3 -C 10
cycloalkyl, up to per-halosubstituted C r C 10 alkyl and up to per-halosubstituted C 3 -C 10
cycloalkyl;
B is a substituted or unsubstituted, up to tricyclic, aryl or heteroaryl moiety of
15 up to 30 carbon atoms with at least one 5- or 6-member aromatic structure containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is a
substituted group, it is substituted by one or more substituents independently selected
from the group consisting of halogen, up to per-halosubstitution, and X„,
wherein n is 0-3 and each X is independently selected from the group
20 consisting of -CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , -SR 5 , -NR 5 R 5 ',
-NR 5 C(0)OR 5 ', -NR 5 C(0)R 5 ', C r C 10 alkyl, C 2 -C 10 alkenyl, C r C 10 alkoxy, C 3 -C 10
cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13 heteroaryl, C 4 -C 23 alkheteroaryl,
substituted C,-C 10 alkyl, substituted C 2 -Ci 0 alkenyl, substituted C r C 10 alkoxyl,
substituted C 3 -C 10 cycloalkyl, substituted C 4 -C 23 alkheteroaryl and -Y-Ar;
42
WO 99/32455 PCT/US98/26082
where X is a substituted group, it is substituted by one or more substituents
independently selected from the group consisting of-CN, -C0 2 R 5 , -C(0)R 5 ,
-C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 *, -N0 2 , -NR 5 C(0)R 5 , -NR 5 C(0)OR 5 ' and halogen up
to per-halosubstitution;
5 wherein R 5 and R 5 ' are independently selected from H, C r C 10 alkyl, C 2 -C 10
alkenyl, C 3 -C 10 cycloalkyl, C 6 -C, 4 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23
alkheteroaryl, up to per-halosubstituted C r C 10 alkyl, up to perhalosubstituted C 2 -C 10
alkenyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14
aryl and up to per-halosubstituted C 3 -C 13 heteroaryl,
10 wherein Y is -O-, -S-, -N(R 5 )-, -(CH 2 )- m , -C(O)-, -CH(OH)-, -(CH 2 ) m O- 5
-NR 5 C(0)NR 5 R 5 '-, -NR 5 C(0)-, -C(0)NR 5 a -0(CH 2 ) m -, -(CH 2 ) m S-, -(CH 2 ) m N(R 5 )-,
-0(CH 2 ) m -, -CHX\ -CXV, -S-(CH 2 ) m - and -N(R 5 )(CH 2 ) m -,
m = 1-3, and X a is halogen; and
Ar is a 5-10 member aromatic structure containing 0-2 members of the group
15 consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by
halogen up to per-halosubstitution and optionally substituted by Z nl , wherein nl is 0
to 3 and each Z is independently selected from the group consisting of -CN,
-C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)NR 5 , -N0 2 , -OR 5 , -SR 5 , -NR 5 R 5 ', -NR 5 C(0)0R 5 ',
-C(0)R 5 , NR 5 C(0)R 5 ', C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl,
20 C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, substituted C r C, 0 alkyl, substituted C 3 -C 10
cycloalkyl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl;
wherein if Z is a substituted group, it is substituted by the one or more
substituents independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -N0 2 , -NR 5 R 5 , -NR 5 C(0)R 5 ' and -NR 5 C(0)0R 5 ', and
25 wherein R 2 is C 6 -C 14 aryl, C 3 -C 14 heteroaryl, substituted C 6 -C 14 aryl or
substituted C 3 -C 14 heteroaryl,
wherein if R 2 is a substituted group, it is substituted by one or more
substituents independently selected from the group consisting of halogen, up to per-
halosubstitution, and V n ,
30 wherein n = 0-3 and each V is independently selected from the group
consisting of -CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 ', -C(0)R 5 ,
-0C(0)NR 5 R 5 ', -NR 5 C(0)0R 5 , -S0 2 R 5 , -SOR 5 , -NR 5 C(0)R 5 ', -N0 2 , C r C 10 alkyl, C 3 -
Cjo cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 24 alkheteroaryl,
WO 99/32455
PCT/US98/26082
substituted Cj-C^ alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 6 -C 14 aryl,
substituted C 3 -C 13 heteroaryl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 24
alkheteroaryl,
where if V is a substituted group, it is substituted by one or more substituents
5 independently selected from the group consisting of halogen, up to per-
halosubstitution, -CN, -C0 2 R 5 , -C(0)R 5 , -C(0)NR 5 R 5 , -NR 5 R 5 ', -OR 5 , -SR 5 ,
-NR 5 C(0)R 5 -NR 5 C(0)OR 5 ' and -N0 2 ;
wherein R 5 and R 5 ' are each independently as defined above.
2. A compound of claim 1, wherein R 2 is substituted or unsubstituted
phenyl or pyridinyl, and the substituents for R 2 are selected from the group consisting
of halogen, up to per-halosubstitution and V n , wherein n = 0-3, and each V is
independently selected from the group consisting of substituted and unsubstituted C r
C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, -N0 2 , -NH 2 , -C(0)-C r6 alkyl, -C^N-CC^
alkyl) 2 , -CCCONH-C^ alkyl, -0-C N6 alkyl, -NHC(0)H, -NHC(0)OH, -N(C re
alkyl)C(0)-C r6 alkyl, -N-(C r6 alkyl)C(0)-C r6 alkyl, -NHC(0)-C r6 alkyl, -OC(0)NH
Q.,, aryl ,_-NHC(0)0-C r6 alkyl, -S(0)-C,- 6 alkyl and -S0 2 -C,- 6 alkyl,
wherein if V is a substituted group, it is substituted by one or more halogen, up
to per-halosubstitution.
10 3. A compound of claim 2, wherein B is up to a tricyclic aromatic ring
structure selected from the group consisting of
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PCT/US98/26082
which is substituted or unsubstituted by halogen, up to per-halosubstitution, and
wherein
n = 0-3 and
each X is independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 ', -NR 5 C(0)0R 5 ', -NR 5 C(0)R 5 ', C r
C 10 alkyl, C 2 _ 10 -alkenyl, C Kl0 -alkoxy, - C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -
C 13 heteroaryl, C 4 -C 23 alkheteroaryl, and substituted C r C 10 alkyl, substituted C 2 . 10 -
alkenyl, substituted C^o-alkoxy, substituted C 3 -C 10 cycloalkyl, substituted C 4 -C 23
alkheteroaryl and -Y-Ar;
wherein if X is a substituted group, it is substituted by one or more
substituents independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 ', -N0 2 , -NR 5 C(0)R 5 , -NR 5 C(0)0R 5 ' and
halogen up to per-halosubstitution;
wherein R 5 and R 5 ' are independently selected from H, C r C 10 alkyl, C 2 _ 10 -
alkenyl, C 3 -C 10 cycloalkyl, C 6 -C H aryl, C 3 -C J3 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23
alkheteroaryl, up to per-halosubstituted Cj-Cjo alkyl, up to per-halosubstituted C 2 . 10 -
alkenyl,_up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14
aryl and up to per-halosubstituted C 3 -C 13 heteroaryl,
wherein Y is - O-, -S-, -N(R 5 )-, -(CH 2 )- m , -C(O)-, -CH(OH)-, -(CH 2 ) m O-,
-NR 5 C(0)NR 5 R 5 '-, -NR 5 C(0)-, -C(0)NR 5 -,.-(CH 2 ) m S-, -(CH 2 ) m N(R 5 )-, -OCCH^-,
-CHX a -, -CX a 2 -, -S-(CH 2 ) m - and -N(R 5 )(CH 2 ) m -,
m = 1-3, and X a is halogen; and
Ar is a 5-10_member aromatic structure containing 0-2 members of the group
consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by
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PCT/US98/26082
halogen up to per-halo substitution and optionally substituted by Z nl> wherein nl is 0
to 3 and each Z is independently selected from the group consisting of -CN,
-C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 ', -NR 5 C(0)OR 5 *,
-NR 5 C(0)R 5 ', C,-C I0 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24
alkaryl, C 4 -C 23 alkheteroaryl, substituted C,-C 10 alkyl, substituted C 3 -C 10 cycloalkyl,
substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl; wherein if Z is a
substituted group, it is substituted by one or more substituents independently selected
from the group consisting of-CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -N0 2 , -NR 5 R 5 ',
-NR 5 C(0)R 5 ' and -NR 5 C(0)OR 5 '.
4. A compound of claim 1 , wherein B is
wherein
Y is selected from the group consisting of -O-, -S-, -CH 2 -, -SCH 2 -, -CH 2 S- 5
-CH(OH)-, -C(O)-, -CX a 2 , -CX a H-, -CH 2 0- and -OCH 2 -,
X a is halogen,
Q is a six member aromatic structure containing 0-2 nitrogen, substituted or
unsubstituted by halogen, up to per-halosubstitution;
Q 1 is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4
members of the group consisting of N, O and S, unsubstituted or unsubstituted by
halogen up to per-halosubstitution,
X, Z, n and nl are as defined in claim 1, and s = 0 or 1 .
5. A compound of claim 4, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-
halosubstitution,
Q 1 is selected from the group consisting of phenyl, pyridinyl, naphthyl,
pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or
unsubstituted by halogen, up to per-halo substitution, or Y-Q 1 is phthalimidinyl
substituted or unsubstituted by halogen up to per-halo substitution, and
WO 99/32455
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PC17US98/26082
Z and X are independently selected from the group consisting of -R 6 , -OR 6
and -NHR 7 , wherein R 6 is hydrogen, C r C 10 -alkyl or C 3 -Ci 0 -cycloalkyl and R 7 is
selected from the group consisting of hydrogen, C 3 -C 10 -alkyl, C 3 -C 6 -cycloalkyl and
C 6 -C l0 -aryl, wherein R 6 and R 7 can be substituted by halogen or up to per-
5 halosubstitution.
6, A compound of claim 1 , wherein R 1 is t-butyl and R 2 is unsubstituted
or substituted phenyl.
7. A compound of claim 4, wherein Q is phenyl, Q 1 is phenyl or
pyridinyl, Y is -O-, -S- or -CH 2 -, and X and Z are independently CI, F, N0 2 or CF 3 .
8. A compound of claim 7, wherein R 1 is t-butyl.
9. A compound of claim 1 of the formula
N
I
N
t-Bu
O
NH-C-NH-B
wherein B and R 2 are as defined in claim 1 .
10. A compound of claim 9, wherein R 2 is selected from substituted and
unsubstituted members of the group consisting of phenyl and pyridinyl, wherein if R 2
is a substituted group, it is substituted by one or more of the substituents selected from
the group consisting of halogen and W n , wherein n = 0-3, and W is selected from the
group consisting of -N0 25 -C 1 - 3 alkyl,-NH(0)CH 3 ,-CF 3 , -OCH 3 , -F,-C1,-NH 2 ,
-OC(0)NH- up to per-halosubstituted phenyl, -S0 2 CH 3 , pyridinyl, phenyl, up to per-
halosubstituted phenyl and C r C 6 alkyl substituted phenyl.
11. A compound of claim 1 of the formula
t-Bu
o
R NH-C-NH-B
WO 99/32455
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PCT/US98/26082
wherein B and R 2 are as defined in claim 1 .
12. A compound of claim 11, wherein R 2 is selected from substituted and
unsubstituted members of the group consisting of phenyl and pyridinyl, wherein if R 2
is a substituted group, it is substituted by one or more substituents selected from the
group consisting of halogen and W nJ wherein n = 0-3, and W is selected from the
group consisting of -N0 2 , -C r3 alkyl, -NH(0)CH 3 , -CF 3 , -OCH 3 , -F, -CI, -NH 2 ,
-S0 2 CH 3 , pyridinyl, phenyl, up to per-halosubstituted phenyl and C r C 6 alkyl
substituted phenyl.
13. A compound of claim 1 of the formula
wherein B and R 2 are as defined in claim 1 .
14. A compound of claim 13, wherein R 2 is selected from substituted and
unsubstituted members of the group consisting of phenyl and pyridinyl, wherein if R 2
is a substituted group, it is substituted by one or more substituents selected from the
group consisting of halogen and W n , wherein n = 0-3, and W is selected from the
group consisting of -N0 2 , -C r3 alkyl, -NH(0)CH 3 , -CF 3 , -OCH 3 , -F, -CI, -NH 2 ,
-S0 2 CH 3 , pyridinyl, phenyl, up to per-halosubstituted phenyl and C x -C 6 alkyl
substituted phenyl.
15. A method for the treatment of disease mediated by raf kinase, comprising
administering a compound of formula I or a pharmaceutically acceptable salt thereof:
t-Bu
o
A-NH-C-NH-B
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PCT/US98/26082
wherein A is a heteroaryl selected from the group consisting of
wherein R 1 is selected from the group consisting of C 3 -C 10 alkyl, C 3 -C 10
cycloalkyl, up to per-halosubstituted C r C 10 alkyl and up to per-halosubstituted C 3 -C 10
cycloalkyl;
B is a substituted or unsubstituted, up to tricyclic, aryl or heteroaryl moiety of
up to 30 carbon atoms with at least one 5- or 6-member aromatic structure containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is a
substituted group, it is substituted by one or more substituents independently selected
from the group consisting of halogen, up to per-halosubstitution, and X„,
wherein n is 0-3 and each X is independently selected from the group
consisting of-CN, C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 ',
-NR 5 C(0)OR 5 ', -NR 5 C(0)R 5 ', C r C 10 alkyl, C 2 _ 10 -alkenyl, C M0 -alkoxy, C 3 -C 10
cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13 heteroaryl, C 4 -C 23 alkheteroaryl,
substituted C r C 10 alkyl, substituted C 2 . 10 -alkenyl, substituted C M0 -alkoxy ^substituted
C 3 -C 10 cycloalkyl, substituted C 4 -C 23 alkheteroaryl and -Y-Ar;
where X is a substituted group, it is substituted by one or more substituents
independently selected from the group consisting of -CN, -C0 2 R 5 , -C(0)R 5 ,
-C(0)NR 5 R 5 , -OR 5 , -SR 5 , -NR 5 R 5 ', -N0 2 , -NR 5 C(0)R 5 ', -NR 5 C(0)OR 5 ' and halogen up
to per-halosubstitution;
wherein R 5 and R 5 ' are independently selected from H, C^-Cto alkyl, C 2 . J0 -
alkenyl, C 3 -Ci 0 cycloalkyl, C 6 -C 14 aryl, C 3 -C, 3 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23
alkheteroaryl, up to per-halosubstituted C r C 10 alkyl, up to per-halosubstituted C 2 _ 10 -
alkenyl ,.up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C 14
aryl and up to per-halosubstituted C 3 -C 13 heteroaryl, wherein Y is - O-, -S-, -N(R 5 )-,
-(CH 2 )- m , -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 5 )-, -0(CH 2 ) ra -,
-CHX\ -CXV, -S-(CH 2 ) m - and -N(R 5 )(CH 2 ) m -,
m = 1-3, and X a is halogen; and
WO 99/32455 49 PCT/US98/26082
Ar is a 5- or 6-member aromatic structure containing 0-2 members of the group
consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by
halogen up to per-halosubstitution and optionally substituted by Z nJ , wherein nl is 0
to 3 and each Z is independently selected from the group consisting of -CN, -C(0)R 5 A
5 -C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)NR 5 , -N0 2 , -OR 5 , -SR 5 , -NR 5 R 5 ', -NR 5 C(0)OR 5 ',
-NR 5 C(0)R 5 , C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24
alkaryl, C 4 -C 23 alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C 10 cycloalkyl,
substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl;
wherein if Z is a substituted group, it is substituted by the one or more
10 substituents independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)NR 5 R 5 , -OR 5 , -SR 5 , -N0 2 , -NR 5 R 5 , -NR 5 C(0)R 5 and -NR 5 C(0)OR 5 ', and
wherein R 2 is C 6 -C 14 aryl, C 3 -C !4 heteroaryl, substituted C 6 -C 14 aryl or
substituted C 3 -C 14 heteroaryl,
wherein if R 2 is a substituted group, it is substituted by one or more
15 substituents independently selected from the group consisting of halogen, up to per-
halosubstitution, and V n ,
wherein n = 0-3 and each V is independently selected from the group
consisting of -CN, -C0 2 R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 *, -OC(0)NR 5 R 5 ' a
-NR 5 C(0)OR 5 ', -NR 5 C(0)OR 5 ', -S0 2 R 5 , -SOR 5 , -NR 5 C(0)R 5 ', -N0 2) C r C I0 alkyl, C 3 -
20 C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C, 3 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 24 alkheteroaryl,
substituted C,-C 10 alkyl, substituted C 3 -C 10 cycloalkyl, substituted C 6 -C 14 aryl,
substituted C 3 -C 13 heteroaryl, substituted C 7 -C 24 alkaryl and substituted C 4 -C 24
alkheteroaryl,
where V is a substituted group, it is substituted by one or more substituents
25 independently selected from the group consisting of halogen, up to per-
halosubstitution, -CN, -C0 2 R 5 , -C(0)R 5 , -C(0)NR 5 R 5 , -NR'R 5 *, -OR 5 , -SR 5 ,
-NR 5 C(0)R 5 ',-NR 5 C(0)OR 5 and -N0 2 ,
wherein R 5 and R 5 ' are each independently as defined above.
16. A method as in claim 15, wherein R 2 is selected from substituted or
unsubstituted members of the group consisting of phenyl and pyridinyl, and the
substituents for R 2 are selected from the group consisting of halogen, up to per-
halo substitution and V n , wherein n « 0-3, and each V is independently selected from
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PCT/US98/26082
the group consisting of substituted and unsubstituted C r C 6 alkyl, C 3 -C 10 cycloalkyl,
C 6 -C 10 aiyl, -N0 2 , -NH 2 , -C(0)-C r6 alkyl, -C(0)N-(C r6 alkyl) 2 , -C(0)NH-C r6 alkyl, -
0-C r6 alkyl, -NHC(0)H, -NHC(0)OH, -N(C r6 alkyl)C(0)-C r6 alkyl, -N-(C r6
alkyl)C(0)-C r6 alkyl, -NHC(0)-C r6 alkyl, -NHC(0)0-C re alkyl, -S(0)-C r6 alkyl
and -S0 2 -C r6 alkyl,
wherein if V is a substituted group, it is substituted by one or more halogen, up
to per-halosubstitution.
17. A method as in claim 15, wherein B is up to a tricyclic aromatic ring
structure selected from the group consisting of
which is substituted or unsubstituted by halogen, up to per-halosubstitution, and
wherein
n = 0-3 and
each X is independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 ', -NR 5 C(0)OR 5 ', -NR 5 C(0)R 5 ', C r
C 10 alkyl, C 2 _i 0 -alkenyl, C MO -alkoxy,_C 3 -Cio cycloalkyl, C 6 -C, 4 aryl, C 7 -C 24 alkaryl, C 3 -
C 13 heteroaryl, Q-C^ alkheteroaryl, and substituted C r C 10 alkyl, substituted C 2 _ 10 -
alkenyl, substituted Cj.^-alkoxy, substituted C 3 -C 10 cycloalkyl, substituted C 4 -C 23
alkheteroaryl and -Y-Ar;
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PCT7US98/26082
wherein if X is a substituted group, it is substituted by one or more
substituents independently selected from the group consisting of -CN, -C0 2 R 5 ,
-C(0)R 5 , -C(0)NR 5 R 5 ', -OR 5 , -SR 5 , -NR 5 R 5 ', -N0 2 , -NR 5 C(0)R 5 ' , -NR 5 C(0)0R 5 ' and
halogen up to per-halosubstitution;
wherein R 5 and R 5 are independently selected from H, C r C, 0 alkyl, C 2 _ 10 -alkenyU
C 3 -C 10 cycloalkyl, C 6 -C H aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl,
up to per-halosubstituted Cj-Cjo alkyl, up to per-halosubstituted C 2 _ 10 -alkenyl, up to
per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted C 6 -C, 4 aryl and up to
per-halosubstituted C 3 -C 13 heteroaryl,
wherein Y is - O-, -S-, -N(R 5 )-, -(CH 2 )- m , -C(O)-, -CH(OH)-, -(CH^O-,
-NR 5 C(0)NR 5 R 5 -, -NR 5 C(0)-, .C(0)M 5 -, -(CH 2 ) m S-, -(CH 2 ) m N(R 5 )-, -0(CH 2 ) m -, -
CHX a -, -CXV, -S-(CH 2 ) m - and -N(R 5 )(CH 2 ) m -,
m = 1-3, and X a is halogen; and
Ar is a 5-10 member aromatic structure containing 0-2 members of the group
consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by
halogen up to per-halosubstitution and optionally substituted by Z nl , wherein nl is 0 to
3 and each Z is independently selected from the group consisting of — CN, -C(0)R 5 ,
-C0 2 R 5 , -C(0)NR 5 R 5 ', -C(0)R 5 , -N0 2 , -OR 5 , - SR 5 , - NR 5 R 5 , -NR 5 C(0)OR 5 ',
-NR 5 C(0)R 5 ', C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24
alkaryl, C 4 -C 23 alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C 10 cycloalkyl,
substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl; wherein if Z is a
substituted group, it is substituted by one or more substituents independently selected
from the group consisting of -CN, -C0 2 R 5 , -C(0)NR 5 R 5 , -OR 5 , -SR 5 , -N0 2 , -NR 5 R 5 ' ,
-NR 5 C(0)R 5 ' and -NR 5 C(0)0R 5 \
18. A method of claim 15, wherein B is
i"
wherein
Y is selected from the group consisting of-O-, -S-, -CH 2 -, -SCH 2 -, -CH 2 S-,
-CH(OH)-, -C(O)-, -CX a 2 , -CX a H-, -CH 2 0- and -OCH 2 -,
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PCT/US98/26082
X a is halogen,
Q is a six member aromatic structure containing 0-2 nitrogen, substituted or
unsubstituted by halogen, up to per-halosubstitution;
Q 1 is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4
members of the group consisting of N, O and S, unsubstituted or unsubstituted by
halogen up to per-halosubstitution,
X, Z, n and nl are as defined in claim 15, and s = 0 or 1.
19. A method as in claim 18, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-
halosubstitution,
Q 1 is selected from the group consisting of phenyl, pyridinyl, naphthyl,
pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or
unsubstituted by halogen, up to per-halo substitution, or Y-Q 1 is phthalimidinyl
substituted or unsubstituted by halogen up to per-halo substitution, and
Z and X are independently selected from the group consisting of -R 6 , -OR 6
and -NHR 7 , wherein R* is hydrogen, Cj-C 10 -alkyl or C 3 -C 10 -cycloalkyl and R 7 is
selected from the group consisting of hydrogen, C 3 -C, 0 -alkyl, C 3 -C 6 -cycloalkyl and
C 6 -C 10 -aryl, wherein R 6 and R 7 can be substituted by halogen or up to per-
halosubstitution.
20. A method as in claim 18, wherein Q is phenyl, Q 1 is phenyl or
pyridinyl, Y is -O-, -S- or -CH 2 -, and X and Z are independently CI, F, N0 2 or CF 3 .
21. A method as in claim 15, which comprises administering a compound
of one of the formulae
t-Bu
or
t-Bu
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PCT/US98/26082
wherein B and R 2 are as defined in claim 15.
22. A method as in claim 21, wherein R 2 is selected from substituted and
unsubstituted members of the group consisting of phenyl or pyridinyl, wherein if R 2 is
t-Bu
a substituted group, it is substituted by one or more substituents selected from the
group consisting of halogen and W n , wherein n = 0-3, and W is selected from the
group consisting of -N0 2 , -C r3 alkyl, -NH(0)CH 3 , -CF 3 , -OCH 3 , -F, -CI, -NH 2 ,
-OC(0)NH- up to per-halosubstituted phenyl, -S0 2 CH 3 , pyridinyl, phenyl, up to per-
halosubstituted phenyl and C,-C 6 alkyl substituted phenyl.
23. A method as in claim 15, comprising administering an amount of
compound of formula I effective to inhibit raf.
24. A pharmaceutical composition comprising a compound of claim 1 and
a pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising a compound of claim 2 and a
pharmaceutically acceptable carrier.
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26082
A. CLASSIFICATION OF SUBJECT MATTER
IPCr6) :C07D 231/38, 403/12, 409/12, 333/36, 307/66
US CL :54S7368.4, 364.7; 549/59, 549/69, 549/473, 549/480
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 548/368,4, 364.7; 549/59, 549/69, 549/473, 549/480
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
CAS ONLINE
C DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
x
Citation of document, with indication, where appropriate, of the relevant passages
US 5,162,360 A (CRESWELL et al.) 10 November 1992, col. 2,
lines 1-67, col. 3, lines 1-50, examples 22-23.
Relevant to claim No.
1-8, 24-25
9-23
I I Further documents are listed in the continuation of Box C. [^] See patent family annex.
"A"
"E"
"L"
■O'
Special categories of cited documents:
document defining the general state of the art which is not considered
to be of particular relevance
earlier document published on or after the international filing date
document which may throw doubts on priority claim(s) or which is
cited to establish the publication date of another citation or other
special reason (as specified)
document referring to an oral disclosure, use, exhibition or other
means
document published prior to the international filing date but later than
the priority date claimed
later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
the principle or theory underlying the invention
document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document is taken alone
document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
document member of the same patent family
Date of the actual completion of the international search
15 APRIL 1999
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks
Box PCT
Washington, D.C. 20231
Facsimile No. (703) 305-3230
Date of mailing of the international search report
1 2 MAY 1999
Authorized o£fiper
DO
Telephone No
(703) 308-1234
Form PCT/ISA/210 (second sheetX-July 1992):
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26082
Box I Observation* where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This international report has not been established in respect of certain claims under Article 17(2Xa) for the following
1. | [ Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
reasons:
Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
3. | | Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This international Searching Authority found multiple inventions in this international application, as follows:
Please See Extra Sheet.
1 . [~x| As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
2.
Q As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite
of any additional fee.
Q As only some of the required additional search fees were timely paid by the applicant, this international search report
only those claims for which fees were paid, specifically claims Nos.:
payment
covers
4 □ N ° required additionai ^arch fees were timely paid by the applicant Consequently, this international search report
restncted to the inventton first mentioned in the claims; it is covered by claims N.
is
los.:
Remark on Protest Q The additional search fees were accompanied by the applicant's protest.
i I No protest accompanied the payment of additional search fees.
Form PCT/ISA/210 (continuation of first sheet(l)XJuly 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26082
BOX II. OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING
This ISA found multiple inventions as follows:
Group I, claim(s)l-25, drawn to pyrazole compounds.
Group II, claim(s) 1-25, drawn to thiophene compounds.
Group III, claim (s) 1-25, drawn to furan compounds.
The inventions listed as Groups I-III do not relate to a single inventive concept under PCT Rule 13.1 because, under
PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: the only
common structural feature of the listed inventions is the NHCONH group. This group is known and does not define an
advancement in the art.
Form PCT/ISA/210 (extra sheetX-July 1992)*